Structure-based optimization of non-peptidic Cathepsin D inhibitors

Bioorg Med Chem Lett. 2014 Sep 1;24(17):4141-50. doi: 10.1016/j.bmcl.2014.07.054. Epub 2014 Jul 25.


We discovered a novel series of non-peptidic acylguanidine inhibitors of Cathepsin D as target for osteoarthritis. The initial HTS-hits were optimized by structure-based design using CatD X-ray structures resulting in single digit nanomolar potency in the biochemical CatD assay. However, the most potent analogues showed only micromolar activities in an ex vivo glycosaminoglycan (GAG) release assay in bovine cartilage together with low cellular permeability and suboptimal microsomal stability. This new scaffold can serve as a starting point for further optimization towards in vivo efficacy.

Keywords: Cathepsin D; Non-peptidic inhibitor; Structure-based design; X-ray structure.

MeSH terms

  • Cathepsin D / antagonists & inhibitors*
  • Cathepsin D / metabolism
  • Crystallography, X-Ray
  • Dose-Response Relationship, Drug
  • High-Throughput Screening Assays
  • Humans
  • Models, Molecular
  • Molecular Structure
  • Protease Inhibitors / chemical synthesis
  • Protease Inhibitors / chemistry*
  • Protease Inhibitors / pharmacology*
  • Structure-Activity Relationship


  • Protease Inhibitors
  • CTSD protein, human
  • Cathepsin D